CLINICAL PHARMACOLOGY
Mechanism of Action
Benazepril and benazeprilat inhibit angiotensin-converting
enzyme (ACE) in human subjects and animals. ACE is a peptidyl
dipeptidase that catalyzes the conversion of angiotensin
I to the vasoconstrictor substance, angiotensin II. Angiotensin
II also stimulates aldosterone secretion by the adrenal
cortex.
Inhibition of ACE results in decreased plasma angiotensin
II, which leads to decreased vasopressor activity and
to decreased aldosterone secretion. The latter decrease
may result in a small increase of serum potassium. Hypertensive
patients treated with benazepril HCl alone for up to 52
weeks had elevations of serum potassium of up to 0.2 mEq/L.
Similar patients treated with benazepril HCl and hydrochlorothiazide
for up to 24 weeks had no consistent changes in their
serum potassium (see PRECAUTIONS).
Removal of angiotensin II negative feedback on renin
secretion leads to increased plasma renin activity. In
animal studies, benazepril had no inhibitory effect on
the vasopressor response to angiotensin II and did not
interfere with the hemodynamic effects of the autonomic
neurotransmitters acetylcholine, epinephrine, and norepinephrine.
ACE is identical to kininase, an enzyme that degrades
bradykinin. Whether increased levels of bradykinin, a
potent vasodepressor peptide, play a role in the therapeutic
effects of benazepril HCl remains to be elucidated.
While the mechanism through which benazepril lowers blood
pressure is believed to be primarily suppression of the
renin-angiotensin-aldosterone system, benazepril has an
antihypertensive effect even in patients with low-renin
hypertension. In particular, benazepril HCl was antihypertensive
in all races studied, although it was somewhat less effective
in blacks than in nonblacks.
Pharmacokinetics and Metabolism
Following oral administration of benazepril HCl, peak
plasma concentrations of benazepril are reached within
0.5-1.0 hours. The extent of absorption is at least 37%
as determined by urinary recovery and is not significantly
influenced by the presence of food in the GI tract.
Cleavage of the ester group (primarily in the liver)
converts benazepril to its active metabolite, Benazeprilat.
Peak plasma concentrations of Benazeprilat are reached
1-2 hours after drug intake in the fasting state and 2-4
hours after drug intake in the nonfasting state. The serum
protein binding of benazepril is about 96.7% and that
of Benazeprilat about 95.3%, as measured by equilibrium
dialysis; on the basis of in vitro studies, the degree
of protein binding should be unaffected by age, hepatic
dysfunction, or concentration (over the concentration
range of 0.24-23.6 mcmol/L).
Benazepril is almost completely metabolized to benazeprilat,
which has much greater ACE inhibitory activity than benazepril,
and to the glucuronide conjugates of benazepril and benazeprilat.
Only trace amounts of an administered dose of benazepril
HCl can be recovered in the urine as unchanged benazepril,
while about 20% of the dose is excreted as benazeprilat,
4% as benazepril glucuronide, and 8% as benazeprilat glucuronide.
The kinetics of benazepril are approximately dose-proportional
within the dosage range of 10-80 mg.
The effective half-life of accumulation of benazeprilat
following multiple dosing of benazepril HCl is 10-11 hours.
Thus, steady-state concentrations of benazeprilat should
be reached after 2 or 3 doses of benazepril HCl given
once daily.
The kinetics did not change, and there was no significant
accumulation during chronic administration (28 days) of
once-daily doses between 5 mg and 20 mg. Accumulation
ratios based on AUC and urinary recovery of benazeprilat
were 1.19 and 1.27, respectively.
When dialysis was started two hours after ingestion of
10 mg of benazepril, approximately 6% of benazeprilat
was removed in 4 hours of dialysis. The parent compound,
benazepril, was not detected in the dialysate.
The disposition of benazepril and benazeprilat in patients
with mild-to-moderate renal insufficiency (creatinine
clearance >30 ml/min) is similar to that in patients
with normal renal function. In patients with creatinine
clearance £30 ml/min, peak benazeprilat levels and
the initial (alpha phase) half-life increase, and time
to steady-state may be delayed (see DOSAGE AND ADMINISTRATION).
Benazepril and benazeprilat are cleared predominantly
by renal excretion in healthy subjects with normal renal
function. Nonrenal (i.e., biliary) excretion accounts
for approximately 11-12% of benazeprilat excretion in
healthy subjects. In patients with renal failure, biliary
clearance may compensate to an extent for deficient renal
clearance.
In patients with hepatic dysfunction due to cirrhosis,
levels of benazeprilat are essentially unaltered. The
pharmacokinetics of benazepril and benazeprilat do not
appear to be influenced by age.
In studies in rats given 14C-benazepril, benazepril and
its metabolites crossed the blood-brain barrier only to
an extremely low extent. Multiple doses of benazepril
did not result in accumulation in any tissue except the
lung, where, as with other ACE inhibitors in similar studies,
there was a slight increase in concentration due to slow
elimination in that organ.
Some placental passage occurred when the drug was administered
to pregnant rats.
Pharmacodynamics
Single and multiple doses of 10 mg or more of benazepril
HCl cause inhibition of plasma ACE activity by at least
80-90% for at least 24 hours after dosing. Pressor responses
to exogenous angiotensin I were inhibited by 60-90% (up
to 4 hours post-dose) at the 10 mg dose.
Administration of benazepril HCl to patients with mild-to-moderate
hypertension results in a reduction of both supine and
standing blood pressure to about the same extent with
no compensatory tachycardia. Symptomatic postural hypotension
is infrequent, although it can occur in patients who are
salt-and/or volume-depleted (see WARNINGS).
In single-dose studies, benazepril HCl lowered blood
pressure within 1 hour, with peak reductions achieved
2-4 hours after dosing. The antihypertensive effect of
a single dose persisted for 24 hours. In multiple dose
studies, once-daily doses of 20-80 mg decreased seated
pressure (systolic/diastolic) 24 hours after dosing by
about 6-12/4-7 mmHg. The trough values represent reductions
of about 50% of that seen at peak.
Four dose-response studies using once-daily dosing were
conducted in 470 mild-to-moderate hypertensive patients
not using diuretics. The minimal effective once-daily
dose of benazepril HCl was 10 mg; but further falls in
blood pressure, especially at morning trough, were seen
with higher doses in the studied dosing range (10-80 mg).
In studies comparing the same daily dose of benazepril
HCl given as a single morning dose or as a twice-daily
dose, blood pressure reductions at the time of morning
trough blood levels were greater with the divided regimen.
During chronic therapy, the maximum reduction in blood
pressure with any dose is generally achieved after 1-2
weeks. The antihypertensive effects of benazepril HCl
have continued during therapy for at least two years.
Abrupt withdrawal of benazepril HCl has not been associated
with a rapid increase in blood pressure.
In patients with mild-to-moderate hypertension, benazepril
HCl 10-20 mg was similar in effectiveness to captopril,
hydrochlorothiazide, nifedipine SR, and propranolol.
The antihypertensive effects of benazepril HCl were not
appreciably different in patients receiving high- or low-sodium
diets.
In hemodynamic studies in dogs, blood pressure reduction
was accompanied by a reduction in peripheral arterial
resistance, with an increase in cardiac output and renal
blood flow and little or no change in heart rate. In normal
human volunteers, single doses of benazepril caused an
increase in renal blood flow but had no effect on glomerular
filtration rate.
Use of benazepril HCl in combination with thiazide diuretics
gives a blood-pressure-lowering effect greater than that
seen with either agent alone. By blocking the renin-angiotensin-aldosterone
axis, administration of benazepril HCl tends to reduce
the potassium loss associated with the diuretic.
CLINICAL STUDIES
Creatinine and Blood Urea Nitrogen: Of
hypertensive patients with no apparent preexisting renal
disease, about 2% have sustained increases in serum creatinine
to at least 150% of their baseline values while receiving
benazepril HCl, but most of these increases have disappeared
despite continuing treatment. A much smaller fraction
of these patients (less than 0.1%) developed simultaneous
(usually transient) increases in blood urea nitrogen and
serum creatinine. None of these increases required discontinuation
of treatment. Increases in these laboratory values are
more likely to occur in patients with renal insufficiency
or those pretreated with a diuretic and, based on experience
with other ACE inhibitors, would be expected to be especially
likely in patients with renal artery stenosis (see PRECAUTIONS,
General).
Potassium: Since benazepril decreases
aldosterone secretion, elevation of serum potassium can
occur. Potassium supplements and potassium-sparing diuretics
should be given with caution, and the patient's serum
potassium should be monitored frequently (see PRECAUTIONS).
Hemoglobin: Decreases in hemoglobin
(a low value and a decrease of 5 g/dl) were rare, occurring
in only 1 of 2014 patients receiving benazepril HCl alone
and in 1 of 1357 patients receiving benazepril HCl plus
a diuretic. No U.S. patients discontinued treatment because
of decreases in hemoglobin.
Other (causal relationships unknown):
Clinically important changes in standard laboratory tests
were rarely associated with benazepril HCl administration.
Elevations of liver enzymes, serum bilirubin, uric acid,
and blood glucose have been reported, as have scattered
incidents of hyponatremia, electrocardiographic changes,
leukopenia, eosinophilia, and proteinuria. In U.S. trials,
less than 0.5% of patients discontinued treatment because
of laboratory abnormalities.
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